Biomedical Engineering Reference
In-Depth Information
progressive tumor. The primary objective of the Phase I
portion of the study was to determine the optimum duration
of infusion and drug concentration of IL-13-PE38 delivered
by CED via 1 or 2 intratumoral catheters prior to surgical
resection of tumor [63,67]. The Phase 2 objective was to
determine the proportion of patients surviving at 6 months.
In Phase 1, cohorts of 3-6 patients received a fixed drug
concentration (0.5
m
g/mL) with escalating duration of
infusion (4-7 days) to determine MTD based on duration.
After determining maximum duration, drug concentration
was escalated from 1.0 to 4.0
m
g/mL in cohorts of 3-6
patients to determine a MTD based on concentration. Tumor
necrosis was assessed 6-13 days after the end of infusion, at
the time of tumor resection. There were no severe drug-
related AE in the 10 treated patients. Five patients experi-
enced AE grade 2-3. Most frequent AE were headache
(70%), hemiparesis (40%), seizures (40%), edema (40%),
and aphasia (30%). Progression-free survival ranged from 6
to 30 weeks and overall survival from 10 to 30 weeks
[20,63].
In all of these studies, intratumoral infusion of IL-13-
PE38 with or without tumor resection in patients with
recurrent or progressing malignant glioma seemed to be
well tolerated and did not result in any grade 3 and 4 AE, or
in any AE in peripheral organs such as liver, kidney, and
lung. Neurological AE during and after toxin infusion were
encountered in a significant proportion of the treated
patients. These included brain edema, meningitis, seizures,
headache, and symptoms of increased intracranial pressure.
All these AE were temporary and mostly controllable by
administration of steroids. In general, IL-13-PE38 doses
(0.5-2
m
g/mL) showing biological activity (e.g., necrosis
on MRI scans) in tumors were below the threshold of
widespread neurotoxicity (4-12
m
g/mL). Selection of
patients without incipient mass effect in the brain (due to
tumor size and/or peritumoral edema) seemed particularly
important in avoiding serious unwanted side effects. Some
prolonged survival was observed in this selected population
of patients [20,65,66].
A multicenter, Phase III, randomized, open label, active
control, parallel assignment efficacy study (PRECISE) was
carried out in order to determine whether overall survival
duration, safety, and quality of life were improved for patients
treated with IL-13-PE38 compared to patients treated with
Gliadel
1
wafers following surgical tumor removal in the
treatment of first recurrence of GBM after initial surgery
and external beam radiation therapy [68,69]. Patients were
randomized 2:1 to receive IL-13-PE38 or Gliadel. IL-13-
PE38 toxin (0.5
m
g/mL, total flow rate 0.75mL/h) was admin-
istered over 96 h via 2-4 intraparenchymal catheters placed
around the surgical cavity after tumor resection. The primary
endpoint was overall survival from the time of randomization.
Secondary and tertiary endpoints were safety and health-
related quality-of-life assessments.
From March 2004 to December 2005, 296 patients were
enrolled at 52 centers. Median survival was 36.4 weeks (9.1
months) for the toxin group and 35.3 weeks (8.8 months) for
the Gliadel group (p
0.476). For the efficacy evaluable
population, the median survival was 45.3 weeks (11.3
months) for toxin and 39.8 weeks (10 months) for Gliadel
(p
¼
0.310). The adverse-events profile was similar in both
arms, except that pulmonary embolism was higher in the
toxin arm (8% vs 1%, p
¼
0.014).
This was the first randomized Phase III evaluation of an
agent administered via CED and the first with an active
control group in GBM patients. There was no survival
difference between IL-13-PE38 toxin administered via
CED and Gliadel wafers placed at the time of surgery.
Drug distribution was not assessed but may be crucial for
evaluating future CED-based therapeutics [68,69].
¼
20.4.4 TransMID-107 (Tf-CRM107)
TransMID-107 (known as TransMID
TM
, KS Biomedix Hold-
ings plc, UK; now Xenova Group plc, UK/Celtic Pharmaceu-
tical Holdings PL, Bermuda), also known as Tf-CRM107 of
KSB-311, is a thioether conjugate of human transferrin (Tf)
with a truncated natural mutant form of diphtheria toxin (DT)
known as CRM-107, which lacks receptor binding [26].
Native DT is produced by the bacterium C. diphtheriae
and is composed of two disulfide-linked subunits, both of
which are involved in itsmechanismof toxicity. TheAsubunit
catalyzes ADP-ribosylation of EF-2, thereby stopping pro-
tein synthesis and killing the cell. The B subunit has two
functions: binding to cell-surface receptors and trans-
location of the A subunit into the cytosol [70]. It has
been shown previously that the binding function of DT
can be separated from the translocation function. Laird and
Groman (1976) published data on the isolation of nontoxic
DT mutants belonging to four major classes, I to IV [71].
Mutant proteins serologically related toDTwere designated
as cross-reacting material (CRM). In the class I CRM-107
mutant, two point mutations (phenylalanine at positions 390
and 525 of the DT sequence) reduced the binding 8000-fold
and its toxicity 10,000-fold, compared to native DT [71,72].
However, conjugation of CRM-107 by thioether linkage to
various new binding moieties was able to reconstitute full
toxicity of the mutant [70]. DT entry via different receptor
molecules was examined and results showed that the DT
receptor was not required for translocation of DT to the
cytosol, and that it apparently had no other function than to
mediate rapid internalization to low pH compartments. The
B chain of DT appeared to contain all the membrane
translocation activity, and this activity was distinct and
separable from the receptor-binding site on the toxin
B subunit [70]. By linking CRM-107 with Tf, a receptor-
ligand complex was created that is rapidly internalized
to an environment
that facilitates toxin translocation.
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